Summary Dysregulated immune responses against commensal bacteria are associated with the pathogenesis or progression of multiple gastrointestinal diseases, and maintaining physical separation between commensal bacteria and the mammalian immune system can prevent this inflammatory response. However, recent reports demonstrate that selective species of commensal bacteria can reside on the interior of intestinal-associated lymphoid tissues of healthy humans, non-human primates and mice. How this unique colonization occurs and functionally influences the immune system is unclear. In new preliminary data, we demonstrate that lymphoid tissue-resident commensal bacteria (LRC) can colonize murine dendritic cells and modulate cytokine production. In germ-free and antibiotic-treated (ABX) mice, LRCs colonize intestinal-associated lymphoid tissues and induce multiple members of the IL-10 cytokine family, including dendritic cell-derived IL-10 and group 3 innate lymphoid cell (ILC3)-derived IL-22. Notably, IL-10 limits the development of pro-inflammatory Th17 cell responses, and IL-22 production enhances LRC colonization in the steady state. Furthermore, LRC colonization protects mice from lethal intestinal damage in an IL-10-IL-10R-dependent manner. Collectively, our data reveal a novel host- commensal bacteria dialogue whereby selective subsets of commensal bacteria interact with dendritic cells to facilitate tissue-specific responses that are mutually beneficial for both the host and the microbe. These findings provoke the central hypothesis that LRC interactions with mammalian dendritic cells critically modulate chronic inflammation in the gastrointestinal tract. We will employ theses approaches to define novel functional interactions between LRCs and mammalian dendritic cells in the context of intestinal health and disease. Two specific aims of this project will determine (i) Do LRCs modulate host nitric oxide production to persist within DCs and influence intestinal damage and inflammation, and (ii) Does DC regulation of intracellular iron modulate colonization by LRCs and subsequent cytokine production during intestinal health and disease? Collectively, these studies will systematically interrogate novel functional interactions between an unappreciated class of commensal bacteria and mammalian hosts. These studies will inform ongoing efforts to develop effective therapies targeting the microbiota to limit chronic gastrointestinal diseases.